In recent years, the wealth of basic science research supporting resveratrol’s potential to treat, delay, and even prevent age-related chronic diseases has led to a number of human clinical trials. While such translational research has yielded promising results in clinical populations, recently published conflicting results from studies evaluating resveratrol’s potential for primary prevention of chronic disease in healthy / asymptomatic individuals have generated considerable controversy and do not initially appear consistent with findings from animal models. We argue that trials targeting healthy humans are often fundamentally flawed owing to inappropriate use of paradigms only applicable to populations with overt clinical disease and the consequent misleading (typically negative) results can severely retard advancement of drug development. To appropriately perform translational research centered on resveratrol as a primary prevention agent in non-clinical populations, it is critical to utilize study designs which can provide adequate information on clinically relevant outcome measures, avoid paradigms and assumptions from interventions which are specific to clinical populations, and maintain realistic expectations compared to interventions which provide the theoretical maximal response (e.g., caloric restriction and aerobic exercise training).
Conflicting findings between basic science and human clinical trials, and between different clinical trials, for resveratrol treatment are due to major differences in research protocols, including inappropriate outcome variables and ineffective dosing protocols, which preclude valid assessment of physiological response within humans Biomarkers which are highly responsive to treatment in individuals with chronic disease (eg, blood pressure, insulin sensitivity) are not likely to be as sensitive to interventions in healthy humans, due to normal homeostatic control mechanisms, and therefore should not be used as clinical endpoints in primary prevention studies in non-clinical populations.
The theoretical maximal response for clinical endpoints to optimal treatments (e.g., exercise training, caloric restriction) must be determined to appropriately interpret response to resveratrol treatment, as these responses will vary depending on the health and age of the cohorts studied.
As optimal dosing of resveratrol may vary for different outcome measures, it is not appropriate to make generalized conclusions regarding resveratrol’s clinical utility in healthy individuals until considerable uncertainties regarding optimal dosing protocols and factors influencing bioavailability are addressed, and its interactions with other primary prevention interventions are thoroughly explored.
Novel methods that incorporate in vitro techniques into human clinical trials, such as whole cell biosensors, can provide a more holistic evaluation of physiologic response.
As long as some human clinical trials continue to produce positive results, resveratrol will remain a popular candidate for the prevention and treatment of chronic diseases. If one searches for a natural compound which consistently transforms ordinary individuals into “superhumans” with optimal physiologic function, inducing similar physiologic adaptations to those observed from caloric restriction or exercise training, resveratrol and other known substances are bound to disappoint. However, if clinical trials are designed such that sufficient sample sizes and study durations are combined with realistic clinical outcome variables, appropriate conclusions may be reached. Only long-term epidemiological studies and meta-analyses can provide more definitive answers on resveratrol’s effectiveness as a primary prevention measure to reduce the incidence, delay the onset, or decrease the severity of chronic diseases. Until then, researchers should be prudent in selecting outcome measures that are sensitive enough to respond to short-to-moderate term resveratrol treatment in healthy individuals. When possible, clinical trials should use multiple formulations or dosages to better determine the optimal administration protocols to achieve the most powerful clinical effects. In addition to exploring the effects of stand-alone resveratrol interventions, it is also important to investigate whether resveratrol can further enhance clinically validated treatments, including existing pharmaceutical treatments and exercise training. Most importantly, assessing factors that contribute to chronic diseases in a sensitive and holistic manner may greatly improve our understanding of the value of resveratrol for primary prevention of cardiometabolic diseases.